Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance

Research output: Contribution to journalArticle

Authors

  • X Yang
  • PP Ongusaha
  • PD Miles
  • JC Havstad
  • F Zhang
  • WV So
  • JE Kudlow
  • JM Olefsky
  • SJ Field
  • RM Evans

Colleges, School and Institutes

Abstract

Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.

Details

Original languageEnglish
Pages (from-to)964-U1
JournalNature
Volume451
Issue number7181
Publication statusPublished - 1 Feb 2008